The extracellular matrix (ECM) is composed of structural and functional components arranged in a three dimensional architecture. Acellular, noncross-linked scaffolds derived from the ECM have been shown to consistently modulate the default mammalian healing response of scar tissue formation towards a more reconstructive type of host response. The mechanisms by which ECM scaffolds modulate the host response towards constructive remodeling as opposed to scar tissue formation are poorly understood;however, it is becoming increasingly clear that mononuclear cell interactions with implanted ECM scaffolds play an important and determinant role in the tissue-remodeling outcome. The present proposal seeks to study the effects of two variables upon the polarization (M1/M2) of macrophages, an important subset of phagocytic mononuclear cells, in response to an implanted ECM scaffold: (1) the presence of a cellular component within the material and (2) the ability of the scaffold to degrade rapidly. Three specific aims are proposed: (1) establish and compare the M1/M2 profile of the host macrophage response to four different scaffolds in a rat body wall model;(2) determine the effect of scaffold degradation upon the resultant M1/M2 profile;and (3) determine the relationship between the M1/M2 profile of the macrophages participating in the host response and the downstream tissue-remodeling outcome associated with the implantation of an ECM scaffold. These specific aims will be achieved by implanting ECM scaffolds, each differing in method of preparation and/or species and organ of origin, in a rat body wall model and assessing both the host macrophage response and the downstream tissue-remodeling outcome via histological, immunohistochemical, and gene expression methods. These results will then be used to determine the relationship between an M1/M2 profile and the downstream tissue-remodeling outcome. ECM scaffolds have been implanted in 1,000,000+ patients to date in applications that include the treatment of partial and full thickness wounds, burns, soft tissue repair, spinal and cranial repair, pelvic reconstruction, and the treatment of urinary incontinence, among others. Therefore, the results of the proposed work to better understand the mechanisms underlying the host response to an ECM scaffold, and the effects that production methods can have on this response, will have immediate clinical relevance. This research will also contribute to the understanding of the role of macrophage polarization within the tissue remodeling paradigm as a whole. The work will be conducted over the course of two years in an environment of strong intellectual stimulation and interdisciplinary activity.